Abstract

Combined therapy of rapamycin and nanoliposomal irinotecan (nLs-CPT-11) was used in the treatment of U87-MG intracranial brain tumor model looking for an improvement in the survival in comparison to animals that received only single-agent therapy.

The prognosis for patients with malignant gliomas has remained dismal, and the median survival for patients with glioblastomas is still less than one year after prognosis despite multidisciplinary use of surgery, chemotherapy and radiotherapy. Combination of two agents had start to be an encouraging option to treat glioblastomas giving better results when two different molecules implicate in tumor progress are inhibited instead than only one. Clinical trials with convection-enhanced delivery (CED) have opened a new window in neuro-oncology to the direct delivery of chemotherapeutics to the central nervous system (CNS), circumventing the blood-brain barrier (BBB) and reducing side effects. In this study, we evaluated a combination of nLs-CPT-11 and rapamycin to enhance efficacy in brain tumor xenograft models, and to establish a combination treatment (systemic rapamycin and CED nLs-CPT-11) capable of improving survival from malignant brain tumors. CPT-11 suppress activity of a key enzyme involved in tumor cell replication, topoisomerase I. Rapamycin inhibits PI3K/Akt/mTOR pathway implied in the regulation of the cell proliferation, cell growth, differentiation, migration and survival. In vitro toxicity experiments were carried out with U87-MG and U251-MG cells. An in vivo survival study was performed for intracranial brain tumor xenograft. The combination displayed excellent efficacy in a survival study 7 days after tumor implantation. Animals in the control group had a median survival of less than 20 days, whereas the combination group triplicates the median survival, surviving at least 70 days all the animals. We conclude that CED of nLs-CPT-11 and systemic rapamycin may be an effective treatment option for malignant gliomas.